Sepracor, Inc.

Seprachem, Inc.

Hemasure, Inc.

Donald L Heefner

Richard F Rossi

Charles M Zepp

Gregory D Cuny

James R Hauske

Michael Z Hoemann

Anita Melikian-Badalian

Gnanasambandam Kumaravel

Chris Hugh Senanayake

Qun Kevin Fang

Roger P Bakale

Paul T Grover

Stephen Alan Wald

Laurence M Melnick

Yun Gao

Roger L Xie

The present invention provides methods and pharmaceutical preparations that inhibit the growth of bacterial microorganisms. Additionally, the present invention provides methods and pharmaceutical preparations that kill bacterial microorganisms.

Antimicrobial agents uses and compositions related thereto

Quinoline-indole antimicrobial agents, uses and compositions related thereto

The present invention provides methods and pharmaceutical preparations that inhibit the growth of bacteria microorganisms. Additionally, the present invention provides methods and pharmaceutical preparations that kill bacterial microorganisms.

Quinoline-indole antimicrobial agents, uses and compositions related

An in vitro method for predicting the identity of distinct, first-generation, drug-resistant, biologically-active, HIV protease mutants that may emerge in vivo in response to a drug targeted thereagainst. In a preferred embodiment, the in vitro method comprises the steps of (a) preparing, in the presence of the drug, a comprehensive library of all first-generation mutants of the protease differing therefrom by at least one and preferably no more than three amino acid substitutions, each of the protease mutants being generated as part of a polyprotein with the HIV reverse transcriptase protein; (b) isolating, in vitro, first-generation, drug-resistant, biologically-active, mutant proteases from said library by assaying for biological activity of the reverse transcriptase protein; and (c) identifying the distinct, first-generation, biologically-active, mutant proteases so isolated. The present invention also relates to an in vitro method for evaluating the efficacy of a drug against a biologically-active mutant or wild-type form of HIV protease, said method comprising the steps of (a) providing a mutant polyprotein, said mutant polyprotein including a biologically-inactive mutant form of the protease linked to HIV reverse transcriptase by one or more sites cleavable by the biologically-active or wild-type form of the protease; (b) adding the drug to the mutant polyprotein; (c) then, adding the biologically-active or wild-type form of the protease to the mutant polyprotein; and (d) then, assaying for the presence of biological activity for reverse transcriptase, whereby the presence of reverse transcriptase activity indicates that the drug is not efficacious against the biologically-active mutant or wild-type form of the protease tested. The present invention further relates to a kit for evaluating the efficacy of a drug against a biologically-active mutant or wild-type form of HIV protease.

In vitro method for predicting the evolutionary response of HIV protease

Processes for preparing a single enantiomer of an .alpha.,.alpha.-disubstituted-.alpha.-hydroxy acetic acid, especially cyclohexylphenylglycolic acid (CHPGA), is disclosed. The processes employ cyclic 1,2-aminoalcohols as chiral auxiliaries by forming diastereomeric esters of aminoalcohols or diastereomeric amides of oxazolidines. ##STR1## Intermediates useful in the process are also disclosed.

Asymmetric grignard synthesis with cyclic 1,2 aminoalcohols

A method for identifying, in vitro, distinct, drug-resistant, biologically-active mutants of a protein that may emerge in vivo in response to a drug targeted against the protein is disclosed. The method involves preparing, by heterologous expression of a library of nucleotide sequences, a complete library of mutant proteins accessible in a single generation. The mutant proteins from the library that are drug resistant are identified. When all the first generation mutants have been identified in the above manner, a combination of drugs can be identified that will block the development of resistance. The same technique allows evaluation of the ultimate clinical efficacy of a drug targeted against the protein by comparing the number of resistant first generation mutants. A preferred protein is an HIV protease.

In vitro method for predicting the evolutionary response of a protein to

Method for inactivating non-enveloped viruses using a viricide-potentiating agent. In a preferred embodiment, the method may be used to inactivate non-enveloped viruses present within a sample of whole blood or a blood product and comprises (a) adding to the blood sample a photoactivatable viricide, such as a psoralen, hypericin, methylene blue, toluidine blue or the like, which, when activated, is effective in inactivating enveloped viruses; (b) adding to the blood sample a viricide-potentiating chemical agent that increases the sensitivity of non-enveloped viruses to the activated viricide; and (c) activating the photoactivatable viricide. Preferably, the viricide-potentiating chemical agent includes a first moiety which possesses an affinity for a component of the non-enveloped virus and a second moiety which includes a lipid tail, the first and second moieties being structurally interrelated so that, when the first moiety becomes associated with a component of the non-enveloped virus, the second moiety penetrates or at least partially surrounds the viral capsid of the non-enveloped virus. Examples of the chemical agent include cationic lipopolyamines, such as dioctadecylamidoglycylspermine.

Method for inactivating non-enveloped viruses using a

Described herein is a process for resolving a racemic (C&gt;3) alkyl (R, S) chroman-2-carboxylate compound useful as intermediates in the synthesis of optically pure pharmaceutical compounds is disclosed. The process utilizes a microbial enzyme derived from Serratia marcescens to catalyze the enantioselective hydrolysis of the (C&gt;3) alkyl (S)-chroman-2-carboxylate enantiomer of the racemic mixture to its corresponding carboxylic acid at a faster rate than the R-enantiomer. An enantiomerically pure S-configured carboxylic acid is thereby formed which can undergo acidic esterification to provide an optically pure (C&gt;3) alkyl (S)-chroman-2-carboxylate intermediate for subsequent pharmaceutical synthesis. The nonhydrolyzed (C&gt;3) alkyl (R)-chroman-2-carboxylate enantiomer can also be isolated to provide an optically pure pharmaceutical precursor.

Optical resolution of alkyl chroman-2-carboxylates

A process for resolving racemic alkyl 1,4-benzodioxan-2-carboxylates useful as intermediates in the synthesis of optically pure pharmaceutical compounds such as (S)-doxazosin is disclosed. The process utilizes a microbial enzyme derived from Serratia marcescens to catalyze the enantioselective hydrolysis of the alkyl (S)-1,4-benzodioxan-2-carboxylate enantiomer of the racemic mixture to its corresponding carboxylic acid at a faster rate than the R-enantiomer. An enantiomerically pure S-configured carboxylic acid is thereby formed for subsequent pharmaceutical synthesis. The nonhydrolyzed alkyl (R)-1,4-benzodioxan-2-carboxylate enantiomer can also be isolated and racemized, and the enzymatic hydrolysis reaction repeated.

Optical resolution of alkyl 1,4-benzodioxan-2-carboxylates using

A process for producing substantially pure R-ketoprofen by the enantioselective hydrolysis of racemic ketoprofen choline ester is disclosed. The process utilizes either intact Beauveria bassiana hyphae or an R-specific ester hydrolase isolated therefrom. The ester hydrolase has an approximate molecular weight of 17,800 daltons and an N-terminal sequence of Ala-Pro-Asp-W-Ile-Ile-Gln-Gly-Leu-Ser-Arg-Ala-X-Asp-Gly-Gln-Asp.

Enantioselective hydrolysis of ketoprofen esters by beauveria bassiana

A process for enantioselectively converting an aldehyde, a bisulfite adduct of an aldehyde or a glycidate to a chiral carboxylic acid is disclosed. The process utilizes a microorganism or an enzyme preparation from a microorganism and is particularly useful for producing NSAIDs of the profen class from readily available precursors. Preferred microorganisms are Gram-negative rod bacteria.

Enantioselective production of chiral carboxylic acids

A biocatalytic method of preparing optically pure precursors of paroxetine and a method of preparing paroxetine therefrom are disclosed. A racemic trans ester precursor compound of paroxetine is first prepared. The racemic trans ester precursor compound comprises a mixture of (3S,4R) and (3R,4S) enantiomers. The (3R,4S) enantiomer is hydrolyzed biocatalytically to the corresponding (3R,4S)-trans carboxylic acid or alternatively, the (3S,4R) enantiomer is biocatalytically hydrolyzed the to (3S,4R)-trans carboxylic acid in a reaction catalyzed by a isolated enzyme or a microorganism. In the first instance, the unhydrolyzed (3S,4R) enantiomer is separated from the (3R,4S)-trans carboxylic acid, whereas in the second instance the (3S,4R)-trans carboxylic acid is separated from the unhydrolyzed (3R,4S) enantiomer. The (3S,4R) enantiomer obtained following the selective hydrolysis is reduced to form a (-)-trans-(3S,4R) primary alcohol precursor of paroxetine. Paroxetine is then formed from the (-)-trans-(3S,4R) primary alcohol precursor.

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Hudson, MA, United States of America

Donald L Heefner